The present invention relates to novel cephem compounds useful as antibacterial agents, salts permissible as medicinal drugs, preparation processes for them and further antibacterial agents having them as effective ingredients.
Cephalosporin type antibacterial agents exhibit a broad antibacterial activity against Gram-positive bacteria and Gram-negative bacterial and various cephasporin compounds have already been synthesized. Among these compounds, however, only few therapeutic agents exhibit the antibacterial activity against Pseudomonas aeruginosa and there is no agent which exhibits potent antibacterial effect broadly from Gram-positive bacterial including staphylococcus aureus to Gram-negative bacterial including Pseudomonas aeruginosa.
Moreover, compounds having the thiochromone skeleton in cephem are disclosed in Japanese Unexamined Patent Publication No. Sho 54-109995, No. Sho 57-165389 and No. Sho 57-165390 and U.S. Pat. No. 3,904,618. These link 2- or 3-position of thiochromone skeleton to part of 7-position side chain of cephem and, with respect to compounds having thiochromone skeleton at 3-position side chain of cephem, synthesis, to say nothing of disclosure and suggestion in specification are not made at all.
Since cephalosporin type antibacterial agents exhibit the selective toxicity only against bacteria and do not affect on the animal cells, they are broadly used for the therapy of infective diseases due to bacteria as antibiotics with less side-effects, thus they are drugs with high usefulness.
In recent, however, glucose-nonfermentable Gram-negative bacillus, in particular, Pseudomonas aeruginosa is often isolated from patients, whose immune power has decreased, as a inflaming bacterium for hard-to-cure infective diseases. On the other hand, in the Gram-positive bacteria, staphylococcus aureus (MRSA) resistant to overall antibacterial agents has clinically become a serious object of public concern.
From such situation, antibacterial agents being well-balanced against both Gram-positive bacteria including MRSA and Gram-negative bacteria including Pseudomonas aeruginosa and yet exhibiting potent antibacterial power are sought.
Aiming at providing novel cephalosporin derivatives having excellent antibacterial power, the inventors diligently studied on novel cephalosporin derivatives having 2-(2-aminothiazole-4-yl)-2-substituted-oxyiminoacetamide group or 2-(5-amino-1,2,4-thiadiazole-3-yl)-2-substituted-oxyiminoacetamide group at 7-position of cephem skeleton and unusual thiochromone skeleton at 3-position through sulfide linkage. As a result, a surprising fact has been found that the compounds of the invention have potent antibacterial activity against Gram-positive bacteria and Gram-negative bacteria, simultaneously have well-balanced road antibacterial spectra against up to Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa resistant to overall antibacterial agents and yet increase also the antibacterial activity, leading to the completion of the invention.
Namely, the inventive compounds having 2-(2-aminothiazole-4-yl)-2-substituted-oxyiminoacetamide group or 2-(5-amino-1,2,4-thiadiazole-3-yl)-2-substituted-oxyiminoacetamide group at 7-position of cephem skeleton and (substituted-thiochromone-2-yl) thiomethyl group at 3-position are novel compounds never found in the literatures and have well-balanced broad spectra and potent antibacterial activity against from Gram-positive bacteria including MRSA to Gram-negative bacteria including Pseudomonas aeruginosa.